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UBC Theses and Dissertations

Effects of thermoneutrality on dysferlin-deficient muscular dystrophy Donen, Graham


Limb-Girdle Muscular Dystrophy (MD) Type 2B (LGMD2B) is a rare form of MD caused by mutations in the dysferlin (DYSF) gene. As an autosomal recessive disorder, LGMD2B can occur in both males and females and is characterized by progressive muscle wasting, eventually leading to ambulatory dysfunction. Unfortunately, no treatment options can cure patients of LGMD2B. One potential factor in the lack of therapies is the absence of humanized animal models for preclinical studies. Current LGMD2B mouse models lack the disease severity typically observed in the human condition. Additionally, LGMD2B mice remain mobile, whereas most patients are non-ambulatory or exhibit a marked decrease in mobility. Developing more humanized animal models of LGMD2B is vital for improvements in LGMD2B research. Recently, our lab has shown that crossing a DYSF knockout mouse with a mouse lacking apolipoprotein E (ApoE), a surface transport lipoprotein, significantly raises plasma cholesterol and correlates with a severe muscle wasting phenotype and marked ambulatory dysfunction. However, LGMD2B patients have an intact ApoE gene, demonstrating a major limitation of this model. Regardless, the DYSF/ApoE double knockout (DKO) mouse provides proof of principle that dyslipidemia plays a factor in LGMD2B pathology and warrants further investigations. Since thermoneutral (TN) housing of wild type mice has been shown to increase plasma lipids significantly when fed a western diet (WD), we hypothesized that TN housing of BLAJ mice, a mild model of LGMD2B, would lead to an exacerbation of muscle wasting when fed a cholesterol-rich WD. Herein, we report that TN BLAJ mice fed a cholesterol-rich WD exhibited the greatest level of fibrofatty replacement, despite not increasing plasma cholesterol. Additionally, thermoneutrality affected LGMD2B mice in a sex-specific manner, with females having significantly more fibrofatty replacement than males. Finally, TN BLAJ mice fed a cholesterol-rich WD had increases in mTORC1 regulated protein synthesis, in addition to a decrease in LC3 mediated autophagy, suggesting an overall decrease in protein turnover within DYSF-null skeletal muscle. In conclusion, this study reveals BLAJ mice to be sensitive to changes in ambient temperature and suggests that alterations in metabolism could be a contributing factor in LGMD2B pathology.

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